First-line pembrolizumab monotherapy significantly improved progression-free survival compared with carboplatin plus paclitaxel in patients with mismatch repair–deficient (dMMR) advanced or recurrent endometrial cancer, according to an interim analysis of the phase III KEYNOTE-C93/GOG-3064/ENGOT-en15 trial presented at the European Society for Medical Oncology (ESMO) Congress 2026 (Abstract LBA12) and simultaneously published by Slomovitz et al in The Lancet. The investigators also reported fewer treatment-related adverse events with pembrolizumab, suggesting its potential as a chemotherapy-sparing treatment option.
Study Details
This multicenter, open-label, randomized trial enrolled 299 patients with inoperable, stage III or IV, persistent, advanced, or recurrent dMMR endometrial cancer at 122 centers across 24 countries. Eligible patients were ≥ 18 years, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had not received prior systemic therapy for advanced disease. Patients were randomly assigned 1:1 to receive pembrolizumab (n = 149) or carboplatin plus paclitaxel (n = 150).
Pembrolizumab was administered intravenously at 400 mg every 6 weeks for up to 18 cycles. Patients in the chemotherapy group received carboplatin at an area under the curve of 5 or 6 mg/mL plus paclitaxel at 175 mg/m² every 3 weeks for six cycles. Patients experiencing disease progression in the chemotherapy group could cross over to receive pembrolizumab. The dual primary endpoints were progression-free survival, assessed by blinded independent central review, and overall survival. Secondary endpoints included objective response rate, duration of response, quality of life, and safety.
Key Results
At the April 2026 data cutoff, median progression-free survival was 38.2 months (95% confidence interval [CI] = 17.9 months to not reached) with pembrolizumab vs 8.4 months (95% CI = 6.8–10.4 months) with carboplatin plus paclitaxel (hazard ratio [HR] = 0.57, 95% CI = 0.42–0.79; P = .0002). Estimated progression-free survival rates were 67% vs 40% at 12 months and 53% vs 30% at 36 months, respectively.
Median overall survival was not reached in either group. Although the hazard ratio numerically favored pembrolizumab (HR = 0.77, 95% CI = 0.52–1.15; P = .10), the difference did not meet the prespecified criterion for statistical significance. Estimated 3-year overall survival was 71% in the pembrolizumab group vs 62% in the carboplatin plus paclitaxel group. Among patients with measurable disease, objective response rates were 64% vs 62%, respectively, and complete response rates were 34% vs 26%. Median duration of response was not reached with pembrolizumab vs 10.2 months with carboplatin plus paclitaxel.
Patient-reported global health status/quality-of-life scores improved by 5.06 points from baseline to week 12 with pembrolizumab and declined by 1.96 points with carboplatin plus paclitaxel, a between-group difference of 7.02 points (95% CI = 2.54–11.50).
Treatment-related adverse events occurred in 71% of pembrolizumab recipients and 98% of carboplatin plus paclitaxel recipients, with grade 3 or higher events reported in 18% vs 51%, respectively. Treatment-related adverse events led to discontinuation in 9% vs 15% of patients. Immune-mediated adverse events or infusion reactions occurred more frequently with pembrolizumab (42% vs 17%). Treatment-related deaths occurred in two patients receiving pembrolizumab and one receiving carboplatin plus paclitaxel.
The investigators concluded: “Pembrolizumab monotherapy demonstrated a statistically significant progression-free survival benefit over carboplatin plus paclitaxel in the first-line setting for dMMR advanced or recurrent endometrial cancer. The findings suggest that pembrolizumab monotherapy may serve as a potential chemotherapy-sparing first-line treatment approach in this setting.”
Brian M. Slomovitz, MD, of GOG Foundation, Philadelphia, Pennsylvania and Division of Gynecologic Oncology, Mount Sinai Medical Center, Miami Beach, Florida, is the corresponding author for The Lancet article.
DISCLOSURE: The study was supported by Merck Sharp & Dohme, a subsidiary of Merck & Co. For full disclosures of the study authors, visit thelancet.com.
